The objective of this research is the development of a variety of peptide "conformational templates" as molecular probes, i.e. relatively rigid scaffolds that satisfy at least three requirements: (i) possess limited 3D structures (limited well-determined 3D conformers); (ii) be readily accessible synthetically, and (iii) able to uniquely orient the peptide side chains (both alpha-beta and beta-gamma bonds) that are believed to transfer most of the information during peptide-receptor interactions. This proposal offers tetracyclic conformational peptide templates based on chimeric amino acid analogs of proline, azaproline, pipecolic, azapipecolic, nipecotic and isonipecotic acids as novel "privileged scaffolds" (chimeric amino acids combine the properties of two amino acids, an example is aminoisobutyric acid that combines the steric properties of D- and L-alanine). The ligands chosen for study are sufficiently small that the potential energy surface can be determined by DFT calculations, and the energy minima and their relative energetics evaluated. This provide the basis for evaluating the number and relative energetics of conformers to be considered in data analysis. Novel compounds will be designed and synthesized to introduce covalent constraints that are able to align the amino-acid side chains of the recognition motif with greatest fidelity and lack of negative steric interaction with the binding site of chemokine receptors will be sought by virtual screening through molecular modeling. Novel uses of electrochemical auxiliaries will allow pendant side chains to be attached after the cyclic templates are assembled. The therapeutic target for development of specific inhibition is the CXCR4 receptor with potential applications as an antiviral and in oncology.